Revolutionizing Cancer Treatment

Key Terms: 

• T-Cell: A cell in the immune system that fights diseases.

• CAR-T Cell: A T-cell that fights cancer cells.

• CAR-T Cell Therapy: Taking specific immune cells known as T-cells and manipulating them to fight cancer cells.

• Zinc Finger Transcription Factor: Proteins that regulate gene expression by binding to specific DNA sequences.

• BCL11A: a transcription factor that plays a vital role in brain development.

• Antigen: A particle that makes the immune system make antibodies.

• T cell exhaustion: This refers to the progressive decline in the effector function of the T cells as a result of a long-term exposure to antigens and chronic inflammation. Persistent exposure to antigens lead to the depletion of CAR-T cells and promote transformation of CD8+T cells into NK-like T cells. 

• Immunogenicity: the ability of a foreign substance, or antigen, to provoke a specific and adaptive immune response from the body’s immune system.

• Gene Editing: Changing genetic material of something by adding, replacing, or subtracting a DNA.

• Autologous: something that originates in the individual’s own body. For example, an autologous transplant involves using the patient’s own cells. 

Introduction 

This article explains CAR-T cell therapy, a method to treat cancer. It also includes how the CRISPR/Cas9 gene-editing tool can improve the effectiveness of the CAR-T cells. It presents the pros and cons of CRISPR-enhanced CAR-T cell therapy, and how improvements could be made. 

What is CAR-T Cell Therapy? 

Scientists have begun development of more effective medicines or treatments, like CAR-T cell therapy. The concept of CAR-T cell therapy is actually quite simple; a doctor extracts specific cells named T-cells from the immune system outside the patient’s body, and some parts of the T-cell are manually changed by scientists. The cells are then able to recognize, target, and kill cancer cells present throughout the body. 

Even though CAR-T Cell therapy is pretty efficient in some people, there are still multiple obstacles, including: 

• Persistence of the cells - The CAR-T cells cannot survive or work long enough.

• Drug resistance - CAR-T cells cannot beat the cancer cells.

• Immune evasion - CAR-T cells are not powerful enough to detect cancer cells.

• Toxic reactions - The patient themselves cannot process CAR-T cells.

• Inability to break through solid tumors - CAR-T cells cannot break through cancer cells.

To solve all of the problems, researchers tried using radiation, chemicals, and even friendly viruses known as oncolytic viruses. Potency of CAR-T cell therapy did improve, but none of the solutions fully resolved the issues. 

Also, due to the cost of producing the cells in the first place, CAR-T cell therapy is still not that widely used. The only method for CAR-T cell therapy to be viable is to improve the quality of the cells and lower the cost of production. 

This is where CRISPR/Cas9 technology comes into play. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeat. It is a gene editing tool, usually used in biology research. In the past, CRISPR was shown to have worked well on prokaryotic cells and human/mammalian cells. It is a cost-effective and precise method of altering genes and is simple as well. Researchers have already started optimizing CAR-T cells with the help of CRISPR technology to make the cells persistent, safe, and efficacious. In fact, learning and applying CRISPR technology on CAR-T cells are a rather large division in the field of CAR-T cell therapy now. 

CRISPR/Cas9 Technology 

CRISPR/Cas9 technology has made designing CAR-T cells easier and more convenient. In recent years, the use of CRISPR/Cas9 technology has steadily increased. Immune checkpoints play a crucial role as regulatory molecules in the immune system. The immune checkpoints stop immune cell activity which prevents autoimmune overreaction. This mechanism enables cancer cells to evade immune attacks. By obstructing the binding between immune checkpoints and their ligands, immune checkpoint inhibitors can restore T cell immune function. 

There are some safety problems that still need to be solved in the application of CRISPR/Cas9 cells. Some concerns are the off-target effects, DNA damage, and immunogenicity. The use of this technology also has the potential to activate p53, which would lead to DNA damage. It does this by impeding the DNA repair pathway and potentially heightening the risk of chromosome fragmentation. There have been investigations involving the editing of human embryonic stem cells and other cell types have revealed that the Cas9 protein can directly interact with the DNA-PK. Also, the use of the CRISPR-Cas system has the potential to make unforeseen structural variations(SVs), including deletions, duplications, and insertions. 

Scientists and researchers are also actively refining CRISPR-Cas9 technology and conducting preclinical and clinical trials to assess the safety and efficacy of this technology. In 2023, The FDA approved the inaugural gene editing therapy, which is known as Casgevy, which utilizes the CRISPR technology. This achievement marks an advancement in the field of biotechnology. When the BCL11A gene undergoes mutations, certain adults have the ability to generate fetal hemoglobin. Casgevy conducted a simulation of this mutation and concluded that it releases fetal hemoglobin. 

Conclusion 

CRISPR/Cas9 technology is a powerful tool that can improve the abilities of CAR-T cells by leaps and bounds. Because it can solve most of the problems demonstrated by CAR-T cells with low cost and high speed, it can make CAR-T cell therapy both powerful in treating cancer and low in price. 

This simplified article was written and reviewed by Pravaranand Purvam and Lin Cui